Carboxylic acyl derivatives of digoxin

ABSTRACT

COMPOUNDS OF THE FORMULA   3-((4-HO,5-((4-HO,5-((4-(R1-COO-),5-HO,6-CH3-TETRAHYDRO-   PYRAN-2-YL)-O-),6-CH3-TETRAHYDROPYRAN-2-YL)-O-),6-CH3-   TETRAHYDROPYRAN-2-YL)-O-),17-(5-(O=)-2,5-DIHYDRO-   FUR-3-YL)ANDROSTANE-12,14-DIOL   R1 IS ALKYL OF 2 TO 12 CARBON ATOMS, HALO(-ALKYL OR 1 TO 4 CARBON ATOMS), ARYL-(ALKYL OF 1 TO 4 CARBON ATOMS), CYCLOALKYL-(ALKYL OF 1 TO 4 CARBON ATOMS) OR CYCLOALKYL OF 3 TO 8 CARBON ATOMS; THE COMPOUNDS ARE USEFUL AS CARDIOTONICS.

United States Patent 3,804,825 CARBOXYLIC ACYL DERIVATIVES 0F DIGOXINWalter Liisel and Herbert Merz, Ingelheim am Rhein, Wolfgang Hoefke,Budenheim, and Werner Traunecker, Munster-Sarmsheim, Germany, assignorst0 Bo'ehringer Ingelheim G.m.b.H., Ingelheim am Rhein, Germany NoDrawing. Filed Jan. 5, 1972, Ser. No. 215,666 Claims priority,application Germany, Jan. 4, 1971,

P 21 01 595.2 Int. Cl. C07c 173/00 US. Cl. 260-2105 11 Claims ABSTRACTOF THE DISCLOSURE Compounds of the formula 15 n n H n wherein R is alkylof 2 to 12 carbon atoms, halo-(alkyl'of 1 to 4 carbon atoms),aryl-(alkyl of 1-to 4 carbon atoms),

cycloalkyl-(alkyl of l to 4 carbon atoms) or cycloalkyl of 3 to 8 carbonatoms;

the compounds are useful as cardiotonics.

This invention relates to novel carboxylic acyl deriva- 40 tives ofdigoxin, as well as to methods of preparing these compounds.

More particularly, the present invention relates to a novel class ofcarboxylic acyl derivatives of digoxin represented by the formulawherein R is alkyl of 2 to 12 carbon atoms, halo-(alkyl of l to 4 carbonatoms), aryl-(alkyl of 1 to 4 carbon atoms), cycloalkyl-(alkyl of 1 to 4carbon atoms) or cycloalkyl of 3 to 8 carbon atoms, and

3,804,825 Patented Apr. 16, 1974 ice The compounds embraced by Formula Imay be prepared by the following methods:

Method A By subjecting a glycoside of the formula wherein R has the samemeaning as in Formula I, to an ester exchange reaction with anortho-ester of the formula wherein R has the same meanings as in FormulaI and R is lower alkyl, to form a cyclic ortho-ester of the for- O R:(IV) wherein R R and R have the meanings defined above, and subjectingthe cyclic ortho-ester to a stereoselective partial hydrolysis reaction.

Method B By reacting a 'glycoside of the Formula II with an acylatingagent of the formula wherein R has the same meaning as in Formula I andX is halogen, acyl or another anionically easily removable radical, andseparating the desired monoacylated digitoxin derivative from theresulting mixture of isomeric monoacylated andpolyacylated digitoxinderivatives pursuant to conventional methods.

The preparation of the cyclic ortho-ester of the Formula IV by method Ais carried out in the presence of an acid catalyst and, if desired, inthe presence of an inert organic solvent, such as'tetrahydrofuran,dioxane, chloroform or "methylene chloride. Suitable acid catalysts areinorganic or strong organic acids, such as hydrohalic acids, sulfuricacid, p-toluenesulfonic acid, 'methansulfonic acid or trichloroaceticacid; Lewis acids, such' as potassium bisulfate, zinc chloride,borontrifiuoride-e'therate or copper sulfate; or acid ion-exchangers,such as Amberlite IR or Dowex 50.

The ester exchange reaction may be performed at a temperature between 0C. and the reflux temperature of the reaction mixture, but preferably atabout room temperature.

The subsequent partial hydrolysis of the intermediate cyclic ortho-esterof the Formula IV is carried out in the presence of an aqueous acid; ifthe intermediate orthoester has previously been isolated, it isredissolved in an inert organic solvent, such as ethyl acetate, prior tobeing subjected to partial hydrolysis.

We have found that it is particularly advantageous to admix the reactionmixture resulting from the ester exchange reaction with the aqueous acidand to perform the partial hydrolysis in situ therein. Any desiredaqueous acid solution having a pH of 4 or less may be used. Thehydrolysis reaction proceeds in stereo-selective fashion, that is, as arule, the hydrolysis product consists uniformly of the derivative withan esterified OH-group in the 3'-position to the exclusion of all othertheoretically possible derivatives.

The acylation of the free hydroxyl group in the C -position by Method Bmay be effected according to any con- 'ventional acylation process,provided the stability of the starting compound of the Formula IIpermits it. For example, it may be effected with a reactive derivativeof the desired acid, such as an acyl halide, an acid anhydride or amixed anhydride of an acid and a carbonic acid monoester, at roomtemperature in the presence of an inert solvent and an acid-bindingagent. Suitable acidbinding agents are inorganic or tertiary organicbases; the latter, such as pyridine, may simultaneously serve as thesolvent medium if they are provided in sufiicient excess.

The reaction product obtained pursuant to Method B consistspredominantly of a mixture of aand fl-acyldigoxin; it may be separatedinto its individual components and purified by conventional methods,such as by column chromatography, Craig-distribution chromatographyand/or fractional crystallization. In order to increase the yield of thedesired a-form, the undesired p-form may be isomerized in an inertsolvent in the presence of an acid catalyst, preferably an acidadsorbent, such as active aluminum oxide.

The starting compound of the Formula II is digoxin, which is a knowncompound [see The Merck Index, 8th ed., page 365 (1968)].

The following examples further illustrate the present invention and willenable others skilled in the art to understand it more completely. Itshould be understood, however, that the invention is not limited solelyto the particular examples given below.

EXAMPLE 1 a-Propionyl-digoxin by Method B 3.22 gm. of digoxin weredissolved in 75 ml. of absolute pyridine, 0.6 ml. of propionic acidanhydride (1.1 molar excess) was added to the solution, and the mixturewas allowed to stand overnight at room temperature. Thereafter, thereaction mixture was poured into from 10 to times its volume of water,the aqueous mixture was vacuum-filtered and the filter cake was washedwith water.

By extraction of the filtrate with chloroform, about 23% of non-acylateddigoxin starting material was recovered.

The filter cake contained, in addition to residual amounts of digoxin,mainly the desired a-propionyldigoxin, as well as B-propionyl-digoxinand a mixture of various higher acylated products. The glycoside mixturewas worked up by repeated column chromatography on silicagel (grain size0.05-0.2 mm.), using as the elution agent chloroform to which increasingamounts (1-10%) of methanol were added.

The progress of the separation was followed on silicagel plates, using achloroform-methanol mixture (90:10) as the flow agent and a chloroformicantimony trichloride solution as the revealing dye.

4 958 mgm. (27% of theory) of a-propionyl-digoxin, M.P. 175-177 C. afterrecrystallization from chloroform/ methanol/ether (15 :3270), of theformula CH3 CH3 were obtained, and 916 mgm. of digoxin were recovered.

EXAMPLE 2 a-Propionyl-digoxin by Method A A mixture consisting of 2 gm.of digoxin, ml. of absolute tetrahydrofuran, 1 ml. of ortho-propionicacid triethyl ester and 50 mgm. of p-toluenesulfonic acid was stirredfor 90 minutes at room temperature. Thereafter, in order to partiallyhydrolyize the cyclic ortho-ester formed thereby, 50 mgm. ofp-toluenesulfonic acid and 2 ml. of water were added to the reactionmixture. After completion of the acid hydrolysis, the reaction solutionwas neutralized by addition of triethylamine and then evaporated todryness in vacuo on a water bath at 50 C. The residue was digested withwater, the aqueous mixture was vacuum-filtered, and the filter cake wasrecrystallized from methanol/chloroform/ether (1:125), yielding 1.95 gm.(about 91% of theory) of a-propionyl-digoxin having a melting point ofl79 C.

EXAMPLE 3 a-Butyryl-digoxin by Method A A mixture consisting of 2 gm. ofdigoxin, 100 ml. of absolute tetrahydrofuran, 1 ml. of ortho-butyricacid triethyl ester and 50 mgm. of p-tolnenesulfonic acid was stirredfor 90 minutes at room temperature. Thereafter, the reaction solutionwas neutralized with triethylarnine, then evaporated to dryness in vacuoon a water bath at 50 C., and the residue was taken up in chloroform,and the resulting solution was briefly shaken with 20 ml. of 0.1 Nhydrochloric acid. The organic phase was separated, washed twice withwater, dried over anhydrous sodium sulfate and evaporated to dryness invacuo. The residue was recrystallized from chloroform/ether (1:5),yielding 1.90 gm. (about 87% of theory) of a-butyryl-digoxin having amelting point of 186-l89 C.

EXAMPLE 4 Using a procedure analogous to that described in Example l,72% of theory of a-(chloro-acetyl) digoxin, M.P. 190-191 C., wereobtained from ortho-chloroacetic acid triethyl ester and digoxin.

EXAMPLE 5 Using a procedure analogous to that described in Example 1,88% of theory of u-(6'-chloro-butyryl)-digoxin, M.P. 176179 C., wereobtained from ortho-fi-chloro- 4 butyric acid triethyl ester anddigoxin.

EXAMPLE 6 EXAMPLE 7 Using a procedure analogous to that described inExample 1, 82% of theory of a-(cyclopentyl carbonyl)- digoxin, M.P.171l73 C., were obtained from orthocyclopentanecarboxylic acid triethylester and digoxin.

EXAMPLE 8 Using a procedure analogous to that described in Example 1,85% of theory of u-(cyclohexyl-carbonyl)-digoxin, M.P. 204-206 C., wereobtained from ortho-cyclohexanecarboxylic acid triethyl ester anddigoxin.

EXAMPLE 9 Using a procedure analogous to that described in Example 1,87% of theory of a-(cyclooctyl-carbonyl)-digoxin, M.P. 157-158 C., wereobtained from ortho-cyclooctanecarboxylic acid triethyl ester anddigoxin.

EXAMPLE 10 Using a procedure analogous to that described in Example l,77% of theory of u-(cyclopentyl-acetyl)-digoxin, M.P. 202 0., wereobtained from ortho-cyclopentylacetic acid triethyl ester and digoxin.

EXAMPLE 11 Using a procedure analogous to that described in Example 1,83% of theory of u-(cyclohexyl-acetyl)-digoxin, M.P. 183186 C., wereobtained from ortho-cyclohexylacetic acid triethyl ester and digoxin.

Using a procedure analogous to that described in Example l, 93% oftheory of u-( 3-phenyl-propionyl)-digoxin, M.P. 197-199 C, were obtainedfrom ortho-pphenylpropionic acid triethyl ester and digoxin.

EXAMPIJE 14 Using a procedure analogous to that described in Example 1,85 of theory of a-(y-phenyl-butyryl)-digoxin, M.P. l63-169 C., wereobtained from ortho-lS-phenylbutyric acid triethyl ester and digoxin.

EXAMPLE 15 Using a procedure analogous to that described in Example 1,73% of theory of a-lauroyl-digoxin, M.P. 190- 191 C., were obtained fromortho-lauric acid trimethyl ester and digoxin.

The compounds according to the present invention, that is, thoseembraced by Formula I above, have useful pharmacodynamic properties.More particularly, the compounds of the instant invention exhibitcardiotonic and especially positive inotropic activities in the isolatedventricle of the guinea pig heart as well as in the heart-lungpreparation, and are therefore useful for the treatment of cardiacinsufiiciency in warm-blooded animals. The cardiotonic activity of thecompounds of the present invention is superior to and their toxicitiessignificantly less than that of g-strophanthidin.

For pharmaceutical purposes the compounds according to the presentinvention are administered to warm-blooded animals [perorally orparenterally as active ingredients in customary dosage unitcompositions, that is, compositions in dosage unit form consistingessentially of an inert pharmaceutical carrier and one effective dosageunit of the active ingredient, such as tablets, coated pills, capsules,wafers, powders, solutions, suspensions, emulsions, syrups,suppositories and the like. One effective cardiotonic dosage unit of thecompounds according to the present invention is from 0.00083 to 0.084mgm./kg. body weight, preferably from 0.002 to 0.034 mgm./kg. bodyweight.

The following examples illustrate a few pharmaceutical dosage unitcompositions comprising a compound of the present invention as an activeingredient and represent the best modes contemplated of putting theinvention into practical use. The parts are parts by weight unlessotherwise specified.

EXAMPLE 16 Tablets The tablet composition is compounded from thefollowing ingredients:

Preparation.--The glycoside is intensively milled with ten times itsweight of lactose, the milled mixture is admixed with the remainingamount of the lactose and the potato starch, the resulting mixture ismoistened with an aqueous 10% solution of the gelatin, the moist mass isforced through a 1.5 mrn.-mesh screen, and the resulting granulate isdried at 40 C. The dry granulate is again passed through a 1 mm.-meshscreen, admixed with the magnesium stearate, and the composition iscompressed into mgm-tablets in a conventional tablet making machine.Each tablet contains 0.25 mgm. of the glycoside and is an oral dosageunit composition with effective cardiotonic action.

EXAMPLE 17 Coated pills The pill core composition is compounded from thefollowing ingredients:

Preparation-The glycoside is intensively milled with ten times itsweight of lactose, the milled mixture is admixed with the remainder ofthe lactose and the corn starch, the mixture is moistened with anaqueous 15% solution of the polyvinylpyrrolidone, the moist mass isforced through a l mm.-mesh screen, and the resulting granulate is driedat 40 C. and again passed through the screen. The dry granulate isadmixed with the magnesium stearate, and the resulting composition iscompressed into 50 mgm.-pill cores which are subsequently coated inconventional manner with a thin shell consisting essentially of amixture of sugar and talcum and finally polished with beeswax. Eachcoated pill contains 0.25 mgm. of the glycoside and is an oral dosageunit composition with efiective cardiotonic action.

7 EXAMPLE 18 Drop solution The solution is compounded from the followingingredients:

Parts a-(6'-chloro-butyryl)-digoxin 0.0125 Saccharin sodium 0.3 Sorbicacid 0.1 Ethanol 30.0 Flavoring 1.0 Distilled water, q.s. ad 100.0

EXAMPLE 19 Hypodermic solution The solution is compounded from thefollowing ingredients:

Parts oc- (6'-phenyl-butyryl) -digoxin 0.25 Polyethyleneglycol 600 700.0Tartaric acid 150.0

Distilled water, q.s. ad (by vol.).... 3000.0

EXAMPLE 20 Suppositories The suppository composition is compounded fromthe following ingredients:

Parts a-(phenyl-acetyD-digoxin 0.25

Lactose 4.75

Suppository base (e.g., cocoa butter) 1695.00

Total 1700.00

Preparation.--The glycoside and the lactose are admixed, and the mixtureis milled. The milled mixture is uniformly stirred with the aid of animmersion homogenizer into the suppository base, which had previouslybeen melted and cooled to 40 C. The resulting composition is cooled to37 C., and 1700 mgm.-portions thereof are poured into cooled suppositorymolds and allowed to harden therein. Each suppository contains 0.25 mgm.of the glycoside and is a rectal dosage unit composition with effectivecardiotonic action.

Analogous results are obtained when any one of the other acylateddigoxins embraced by Formula I was substituted for the particularacylated digoxin in Examples 16 through 20. Likewise, the amount ofactive ingredient in these illustrative examples may be varied toachieve the dosage unit range set forth above, and the amounts andnature of the inert pharmaceutical carrier ingredients may be varied tomeet particular requirements.

While the present invention has been illustrated with the aid of certainspecific embodiments thereof, it will be readily apparent to othersskilled in the art that the invention is not limited to these particularembodiments, and that various changes and modifications may be madewithout departing from the spirit of the invention or the scope of theappended claims.

We claim: 1. A compound of the formula CIH: (IIH:

H H O K H H H H H H l! H O=(|JO H HO H 2 wherein R is alkyl of 2 to 12carbon atoms, chloro- (alkyl of l to 4 carbon atoms), phenyl-(alkyl of 1to 4 carbon atoms), cycloalkyl of 5 to 6 carbon atoms (alkyl of 1 to 4carbon atoms) or cycloalkyl of 3 to 8 carbon atoms.

2. A compound according to claim 1, wherein R is alkyl of 2 to 12 carbonatoms, chloro-(alkyl of 1 to 3 carbon atoms), phenyl-(alkyl of 1 to 3carbon atoms), (cycloalkyl of 5 to 6 carbon atoms), methyl or cycloalkylof 3 to 8 carbon atoms.

3. A compound according to claim 2, which is a- (chloro-acetyl)-digoxin.

4. A compound according to claim 2, which is acpropionyl-digoxin.

5. A compound according to claim 2, which is abutyryl-digoxin.

6. A compound according to claim 2, which is tat-(6'- chloro-butyryl)-digoxin.

7. A compound according to claim 2, which is a-(5'-phenyl-butyryl)-digoxin.

8. A compound according to claim 2, which is a- (phenyl-acetyl)-digoxin.

9. A compound according to claim 2, which isa-(cyclopentyl-acetyl)-digoxin.

10. A compound according to claim 2, which is alauroyl-digoxin.

11. A compound according to claim 2, which is a- (cyclohexyl-carbonyl)-digoxin.

References Cited UNITED STATES PATENTS 3,531,462 9/1970 Satoh et a1.260210.5

JOHNNIE R. BROWN, Primary Examiner US. Cl. X.R. 424-182 l! W050 UNITEDsTATEs PATENT .omcE

h CERTIFICATE OF CORRECTIQN Patent No. 31 3 5 Dated April 16, 197 4 aWALTER LUSEL, HERBERT MERZ, WOLFGANG HOEFKE, WEIEIEER TRAUNECKER It iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

Col. 2 line 6h,p"methansulfon1c" should read methanesulfonic A C01. '4line 11, the subscript "2" after closing bracket is missing 901. li ne67 5 H H F H 5 7 Y. 7 I should read H 7 '1 n g u XV- Signed and sealedthis 29th day of ()ctober 1974.

SEAL) T Attesta McCOY M. GIBSON JR c. MARSHALL DANN Attestirag OfficerCommissioner of Patents

